GLI1-induced mammary gland tumours are transplantable and maintain major molecular features

Increased expression of GLI1, the main Hedgehog signalling pathway effector, is related to unfavourable prognosis and progressive disease of certain breast cancer subtypes. We used conditional transgenic mice induced to overexpress GLI1 in the mammary epithelium either alone or in combination with deletion of one Trp53 allele to address the role of elevated GLI1 expression in breast tumour initiation and progression. Induced GLI1 expression facilitates mammary gland tumour formation and this was further increased upon heterozygous deletion of Trp53. The GLI1-induced primary tumours were of different murine molecular subtypes, including Normal-like^Ex, Class8^Ex, Claudin-Low^Ex and Erbb2-like^Ex. The gene expression profiles of some of the tumours correlated well with the PAM50 subtypes for human breast cancer. Whole-exome sequencing revealed somatic mutation profiles with only little overlap between the primary tumours. Orthotopically serially transplanted GLI1-induced tumours maintained the main morphological characteristics of the primary tumours for ≥10 generations. Independent of Trp53 status and molecular subtype, the serially transplanted GLI1-induced tumours were able to grow both in the absence of transgenic GLI1 expression and in the presence of the GLI1 inhibitor GANT61. These data suggest that elevated GLI1 expression has a determinant role in tumour initiation; however, additional genetic events are required for tumour progression.     

Clinical characteristics and surgical treatment of sporadic primary hyperparathyroidism with emphasis on chief cell hyperplasia

In 570 patients with sporadic primary hyperparathyroidism, the age, sex, symptoms, and preoperative serum calcium values were related to the histopathologic diagnoses, operative findings, and the extent and outcome of parathyroid surgery. Renal stone formation was especially prevalent in younger patients with slight hypercalcemia and parathyroid chief cell hyperplasia, whereas neuromuscular and psychiatric disturbances were overrepresented among older women with higher serum calcium values. Serum calcium concentration was inversely correlated to the proportional incidence of chief cell hyperplasia and positively correlated to the glandular weight of both adenomas and hyperplasias. Glandular size was markedly irregular in chief cell hyperplasia, with increased gland weights of no more than two glands in 78% of patients. During follow-up, for as long as 27 years, normocalcemia was obtained in 91% of patients with adenomas, with failures mainly depending on difficulties in identifying the parathyroid glands. The rate of normocalcemia was lower (80%) among patients with hyperplasia, but an inability to visualize the glands was not a major cause of failure. In patients with hyperplasia with asymmetric and more markedly enlarged glands, it appeared sufficient to remove only the enlarged glands, whereas the findings advocated a subtotal 3- to 3.5-gland resection in patients with more symmetrically or less enlarged hyperplastic glands.     

MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography

Objective: The aim of the study was to investigate whether or not esuprone binds substantially to MAO-A in the human brain. Methods: In a randomised double-blind placebo-controlled study 16 male healthy volunteers were examined␣with positron emission tomography (PET) with [¹¹C]harmine. Eight of the volunteers were given daily doses of 800 mg esuprone, four were given bi-daily doses of 300 mg moclobemide, and four volunteers were given placebo tablets. PET was performed before initiation of a 7-day treatment period. On day 7, one investigation was made immediately before administration of the drug, representing 23 h after the previous day's treatment for esuprone and 11 h after the last tablets of moclobemide. Further investigations were made 4 h and 8 h after the morning dose on day 7. Results: PET showed a high degree of binding of [¹¹C]harmine, a high-affinity ligand for MAO-A, before the start of treatment, and a marked and similar reduction after treatment with esuprone and moclobemide. A slight tendency for normalisation of enzyme binding was observed at the last time point. In the placebo group no change was observed. Plasma kinetics of esuprone showed a rapid elimination with a half-life of about 4 h. Conclusion: The study demonstrates that esuprone was comparable to moclobemide in its effect on MAO-A inhibition in the brain at the doses given. This is an illustration of the potential of PET to monitor drug effects directly on target biochemical systems in the brain in human volunteers, and the possibility of using these data, rather than pharmacokinetic data, for the determination of dosing intervals. Received: 21 August 1996 / Accepted in revised form: 22 November 1996     

An adaptor to the Leksell stereotaxic instrument for digital coordinate determination in radiography

Summary Special perspex adaptors with radiopaque reference structures have been constructed to fit to the Leksell stereotaxic instrument. These structures are visualized on X-ray film in a radiographic examination like angiography or encephalography. The films obtained in two projections at arbitrary angles and focus-film-distances are placed on a digitizing table for the determination of the stereotaxic coordinates of selected targets. The reference structures and the targets are marked with a cursor whereupon a desk top computer performs the calculation of the stereotaxic coordinates. The system allows a rapid, simple and accurate coordinate determination in stereotaxic radiography using the Leksell stereotaxic instrument.     

Lung cell reactions in guinea pigs after inhalation of asbestos (amosite)

To study the long-term effect of inhaled asbestos, guinea-pigs were exposed to airborne amosite at a concentration of 49 mg/m3, 2 h/day for 3 or 6 weeks and examined up to 2 years after exposure. Macrophages in lung lavage fluid (LLF) were increased at 16, 24 and 93 weeks and lymphocytes at 24 weeks. Examination of lung wall cells (LWC) 2 years after exposure compared to cells obtained by LLF showed higher proportions of LWC lymphocytes and neutrophils. Percoll gradient centrifugation of these cells showed a higher proportion of high density macrophages in LLF from the amosite-exposed animal and an increased number of low density lymphocytes in the LW. Cathepsin D was increased in LLF at 8 and 24 weeks and in alveolar macrophages 24 weeks and 2 years after exposure. Fibroblast cultures exposed to LLF did not show any statistical significant changes in their collagen synthesis. Histology 93 weeks after exposure showed macrophage and mediastinal lymph node accumulation of asbestos, as well as collagen in alveolar walls. Granulomas were found in the vicinity of blood vessels and in connection with the bronchioles. The data suggest that amosite at low doses ultimately causes fibrosis with a reaction pattern different from that seen in silicosis. The inflammation and fibrosis seems to develop only within the interstitium.     

Mercury exposure of different origins among dentists and dental nurses

Mercury exposure was studied among dental personnel with the use of urinary mercury excretion rates and questionnaires. The study covered 314 dentists and dental nurses employed in public clinics and private practices in Stockholm. The obtained urinary mercury excretion rates were analyzed by stepwise regression for assigning them to different origins, such as environmental factors, number of amalgam surfaces, chewing of gum, kind of employment and profession, age, sex, amalgam handling time, and use of amalgam capsules. On the average the occupational contribution to the total urinary mercury excretion rate was small and of the same order as the contribution from their own amalgam fillings (approximately 2 micrograms of mercury/24 h). There were, however, individuals showing excretion rates close to the levels at which effects on the central nervous system and the kidneys have been reported.     

External cephalic version and daily post-versional maternal self-assessment of fetal presentation. A prospective study.

External cephalic version (ECV) using tocolysis is a widely recognized low-risk intervention in cases of breech presentation, particularly in areas where resources are scarce and the perinatal mortality is high in vaginal breech deliveries. In such a setting, pregnant women were trained to make regular self-assessments of the presenting fetal part after ECV in order to detect spontaneous reversions to breech presentation. It was found that such maternal involvement could significantly improve the final results of ECV.     

Is the humoral renal antihypertensive activity of the spontaneously hypertensive rat (SHR) reset to the high blood pressure?

The kidneys have a humoral antihypertensive system, located in the renal medulla and presumably antagonizing the pro-hypertensive renin-angiotensin system. Medullipin I and II and maybe platelet activating factor (PAF), seem to be the mediators of this system, known to be activated after reversal of renovascular hypertension or when the perfusion pressure to a normotensive kidney is suddenly elevated. The present study was undertaken to investigate whether this system is functioning also in the spontaneously hypertensive rat (SHR), and if it is then reset in proportion to the increased mean arterial pressure (MAP). Isolated kidneys from spontaneously hypertensive rats and from Wistar Kyoto rats (WKY) were cross-perfused in vivo from anaesthetized intact Wistar Kyoto rat 'donors'. After 30 min of perfusion at 100 mmHg the perfusion pressure to the isolated kidneys were, for 60 min, either kept unaltered at 100 mmHg or, for the Wistar Kyoto rat kidneys, increased to 150-200 mmHg and, for the spontaneously hypertensive rat kidneys, raised to 200 or 250 mmHg. The results show that the humoral antihypertensive system is present also in spontaneously hypertensive rat kidneys, but is here reset upwards to or even beyond the elevated MAP level. Furthermore, all mean arterial pressure reductions caused by high-pressure perfusion of Wistar Kyoto and spontaneously hypertensive rat kidneys were accompanied by reductions in heart rate (HR) in the 'donors', in agreement with previous observations after reversing renal hypertension and after i.v. medullipin I injection. In fact, in spontaneously hypertensive rat kidneys, the 'incretory' depressor mechanism appears to be more markedly reset upwards than is the 'excretory' depressor mechanism inherent in pressure diuresis with consequent salt-volume elimination. In conclusion spontaneously hypertensive rats, like Wistar Kyoto rats and Wistar rats, have a humoral antihypertensive system in the kidneys, but it is reset upwards even beyond the elevated mean arterial pressure level in spontaneously hypertensive rats. The combination of a depressor response and reduced heart rate in the 'donors' renders further evidence that the medullipins are the principal, though probably not the only, humoral antihypertensive factors released from the cross-circulated kidneys.     

Muscle alkali-soluble protein, carnitine, water and electrolytes in patients with persistent post-operative infection

The muscle contents of water, electrolytes, creatine, alkali-soluble protein (ASP) and carnitine were determined using percutaneous muscle biopsy technique. Seven patients with prolonged catabolic states and subsequent respiratory failure were studied. Twelve age- and sex-matched healthy subjects were used for comparison. The muscle content of alkali-soluble protein in relation to the content of DNA was less than half of control values, indicating a loss of more than 50% of muscle protein content. The muscle carnitine content was 25.9 +/- 6.5 mumol/g alkali-soluble protein, suggesting a preserved muscle carnitine concentration. Total muscle water was increased by over 20%, mainly due to an increase in extracellular water. Muscle sodium and chloride contents were doubled. The content of magnesium was slightly reduced but muscle potassium was normal. The marked depletion of muscle protein may have contributed to the requirements for artificial ventilation and the difficulties in weaning off the ventilator. The increase in muscle water masks the loss of metabolically active muscle tissue yielding low values for energy expenditure when relating to body weight. The benefit of the use of the ASP/DNA ratio in nutritional assessment is emphasised.